Pharmaceutical identification

ABSTRACT

Disclosed are methods for marking a pharmaceutical product, container or pharmaceutical packaging system with a scent to establish the identity and/or source of the pharmaceutical.

This application is a continuation of U.S. patent application Ser. No.10/698,981, filed on Oct. 31, 2003, which claims priority from U.S.provisional application No. 60/422,567, filed on Oct. 31, 2002, thedisclosures of both are hereby incorporated by reference in its theirentirety.

FIELD OF INVENTION

The present invention relates to a method of marking pharmaceuticals byadding to the product, container or packaging system, a scent toestablish the authenticity and/or source of the pharmaceutical.

BACKGROUND OF THE INVENTION

Authentic pharmaceuticals are vulnerable to being diverted from e.g.,legal pathways of distribution, for reasons of abuse (e.g. stealingpills to get high or to maintain addiction) or for unauthorizeddistribution and illegal sale (e.g, selling pharmaceuticals for profiton the gray market). When pharmaceuticals are misused or abused, theypotentially pose danger to those who choose to use them in a mannerother than as directed by a physician.

When law enforcement intercepts these diverted products, it may bedifficult to determine their origin since they may not be in theiroriginal packaging. When a product is diverted, it is important to beable to identify/trace its origin in order to investigate and remedy thebreakdown in integrity. A diffuse investigation wastes both time andresources (e.g. conducting searches of one factory, when the breech isin another factory). A delay in remedying the source of the diversionand/or counterfeiting can create more economic and personal harm.Remedying the problem quickly may serve to prevent further unintentionalor intentional risk from misuse or abuse. Being able to authenticate theproduct and trace its manufacturing source may help to identify a breechin integrity quickly and efficiently.

Many pharmaceuticals are vulnerable to counterfeiting and falseliability based on product substitution. After customers have acquiredtrust in products provided with a particular visually distinctiveappearance, the products become vulnerable to counterfeiting, since avisually distinctive appearance can be susceptible to being imitated.Typically, a counterfeit product is made to resemble the genuine productas closely as possible with a view to misleading the purchaser intobelieving that the genuine product is being bought. Patients,pharmacists, wholesalers, and manufacturers may not be able to determinethat the product is a counterfeit. Customers buy the counterfeit productwith the expectation that they are buying the genuine product, withpotentially life-threatening consequences, since the counterfeit may notmeet the governmentally approved standard of quality, by providingtreatment that is excessively potent, sub-therapeutic, ornon-therapeutic. Being able to authenticate a product would assurequality and reduce risk. A method for marking a pharmaceutical that isnot easily imitated or counterfeited, would help to authenticate theproduct.

There exists a need in the art, for compositions and methods of markinga pharmaceutical in a safe and reliable manner other than one thatidentifies it visually. In an effort to reduce misuse, abuse anddiversion, and to comply with a risk management program, a new method ofauthentication and sourcing is disclosed.

All documents cited herein are hereby incorporated by reference in theirentireties for all purposes.

OBJECTS AND SUMMARY OF THE INVENTION

It is an object of the invention to provide a method for marking apharmaceutical formulation so that it can be identified by use of anidentifying means. The pharmaceutical formulation can be anypharmaceutical formulation that can benefit by such marking such as,e.g., a pharmaceutical formulation subject to counterfeiting, diversionand/or abuse. In one non-limiting embodiment, the pharmaceuticalformulation is an opioid or non-opioid analgesic formulation.

It is a further object of certain embodiments of the present inventionto provide a method for authenticating a pharmaceutical formulation byidentifying the presence of a scent associated with the pharmaceuticalformulation.

It is a further object of certain embodiments of the present inventionto provide a packaged pharmaceutical formulation such that theformulation in the package can be identified by its scent.

It is a further object of certain embodiments of the present inventionto provide a pharmaceutical packaging system comprising a scent thatenables authentication of the pharmaceutical formulation containedtherein.

It is a further object of certain embodiments of the present inventionto provide a pharmaceutical formulation comprising a scent that enablesauthentication of the pharmaceutical formulation.

The above objects of the invention and others can be achieved by virtueof the present invention, which is directed in part to a method ofmarking a pharmaceutical product with a scent for such identification orauthentication.

In certain embodiments, the present invention is directed to a method ofproviding a scent to a pharmaceutical packaging system containing apharmaceutical formulation, such that the pharmaceutical formulation isidentifiable by the inclusion of the scent.

In certain embodiments, the present invention is directed to a packagingsystem comprising a pharmaceutical formulation, the packaging systemfurther comprising a scent or aroma that can be used to identify thepharmaceutical formulation.

In certain embodiments, the present invention is directed to apharmaceutical packaging system comprising a scent releasant. In certainpreferred embodiments, the scent releasant is activated to release thescent each time the package is opened.

In certain embodiments, the present invention is directed to a methodfor identifying a pharmaceutical product comprising detecting a scentimparted to a pharmaceutical container containing a pharmaceuticalformulation.

In certain embodiments, the present invention is directed to a methodfor providing for the identification a pharmaceutical product comprisingimparting a scent to a pharmaceutical container containing apharmaceutical product, the scent indicating the identity or source ofthe pharmaceutical product.

In certain embodiments, the present invention is directed to a methodfor providing for the identification a pharmaceutical product comprisingimparting a scent to a pharmaceutical container adapted for containing apharmaceutical product, the scent indicating the identity or source ofthe pharmaceutical product; and depositing the pharmaceutical productinto the pharmaceutical container.

In certain embodiments, the present invention is directed to a methodfor identifying a pharmaceutical product comprising detecting prior toadministration with an olfactory measuring device, a scent imparted to apharmaceutical formulation.

In certain embodiments, the present invention is directed to a methodfor identifying a pharmaceutical product comprising detecting prior toadministration with a non-human mammal, preferably a canine, a scentimparted to a pharmaceutical formulation.

In certain embodiments, the present invention is directed to apharmaceutical packaging system comprising a scent releasant means inthe form of a reservoir from which the scent is released each time thereservoir is activated. The scent releasant means is preferablyactivated by the mechanics of opening the pharmaceutical packagingsystem and the scent is then released. In certain embodiments, when thepackaging system is closed, the scent releasant is preferablyde-activated and scent release is decreased or terminated.

In certain embodiments of the present invention, the packaging systemcomprises a pharmaceutical formulation containment portion; apharmaceutical formulation closure portion (e.g., a cap), wherein theclosure portion is removed from the containment portion to gain accessto a pharmaceutical formulation that is to be contained therein; and ascent releasant means. For example, the scent releasant means can have apeel seal in contact with the containment portion and the closureportion, wherein the peel seal seals the scent in a scent reservoir.When the closure portion is removed from the containment portion, thepeel seal peels away from, or otherwise makes accessible to theatmosphere, the scent reservoir and releases the scent or allows it tovolatilize into the air. Upon closure of the package, the peel sealreseals the reservoir preventing or minimizing further release orvolatilization of the scent.

In certain embodiments, the scent for use in the present invention is ina quantity that is physiologically difficult, preferably physiologicallyimpossible, to perceive by the human sense of smell, but which issufficient to either be perceived by a non-human animal such as ascent-trained canine, or detected by an olfactory measuring devicecapable of identifying the scent emitted. For example, in certainembodiments, the amount of scent included in the pharmaceuticalformulation and/or packaging system can be determined using the humanolfactory threshold of a scent as described in M. Devos, et al.,Standardized Human Olfactory Thresholds, 1990, the disclosure of whichis hereby incorporated by reference.

In certain embodiments, the pharmaceutical formulation or pharmaceuticalpackaging system comprises the scent in sequestered form. In suchembodiments, the scent is preferably not detectable unless the integrityof the pharmaceutical dosage form, or the integrity of thepharmaceutical packaging system, is compromised. In certain embodiments,“compromising the integrity of the pharmaceutical dosage form” includescrushing the dosage form (e.g., with a mortar and pestle), therebyallowing the scent to be released, or to be released in a detectablequantity. In certain further embodiments, “compromising the integrity ofthe pharmaceutical packaging system” includes, for example, opening(e.g., cutting or tearing open) the packaging system.

In certain preferred embodiments, the present invention is directed to amethod of preventing counterfeiting of a pharmaceutical formulationcomprising preparing, marketing, and/or distributing in commercialchannels a pharmaceutical formulation as disclosed herein.

In certain preferred embodiments, the present invention is furtherdirect to a method of preventing diversion of a pharmaceuticalformulation comprising preparing, marketing, and/or distributing incommercial channels a pharmaceutical formulation as disclosed herein.

In certain embodiments, the present invention is further directed to amethod of providing a marker to a pharmaceutical product that candistinguish between different batches of the pharmaceutical product,comprising adding one or more different scents (i.e., a “scent profile”)to different batches of the pharmaceutical product to indicate theparticular date or location of manufacture of the pharmaceuticalproduct, wherein the scent is added either to a pharmaceutical productor to a pharmaceutical packaging system containing the product. Forexample, the inclusion of a plurality of scents in a pharmaceuticalproduct or packaging can increase the complexity, and thus theinformational content, in the scent profile of that product, therebyallowing a determination, e.g., of product source, manufacturing date,batch number, etc, of the scent profile.

In certain further embodiments, in addition to the one or more scents,one or more additional identifiers or authenticators are included in thepharmaceutical formulation and/or packaging system. In certain preferredembodiments, in addition to the scent(s), the pharmaceutical formulationor packaging system further comprises an additional marker such as ahapten or plurality of haptens to provide for the further identificationor authentication of the pharmaceutical formulation. In certainpreferred embodiments, the additional marker may be a hapten covalentlybound to a chemical compound in the pharmaceutical formulation or thepharmaceutical packaging system. In certain preferred embodiments, theadditional marker has a detectable physical characteristic such as,e.g., color, weight, density, magnetic attraction, luminescence,fluorescence, absorbance, chemical reactivity, or variouscharacteristics detectable by optical methods known in the art. Incertain embodiments, the use of different scents, or different markersin addition to a scent, can provide different bits of information. Forexample, a first scent in the formulation, container, and/or packagingcan be an indicator of source, while a second scent in the formulation,container, and or packaging can be an indicator of the batch.

In certain embodiments, the invention is directed to a method formarking a pharmaceutical formulation comprising imparting a scent to apharmaceutical product; the scent being undetectable by the human senseof smell, but detectable by a non-human animal or an olfactory measuringdevice, and the scent indicating the identity of the pharmaceuticalproduct, the source of the pharmaceutical product, or a combinationthereof.

In certain embodiments, the invention is directed to a method formarking a pharmaceutical formulation comprising imparting a scent to apharmaceutical container adapted to contain a pharmaceutical product;the scent being undetectable by the human sense of smell, but detectableby a non-human animal or an olfactory measuring device, and the scentindicating the identity of the pharmaceutical product, the source of thepharmaceutical product, or a combination thereof.

In certain embodiments, the invention is directed to a method ofidentifying a pharmaceutical formulation comprising varying the identityof a scent imparted to the pharmaceutical formulation; the scent beingvaried by the manufacturer of the formulation according to apredetermined schedule to indicate when and/or where the pharmaceuticalformulation was manufactured, bottled or packaged.

In certain embodiments, the invention is directed to a method forconducting a pharmaceutical business, comprising a) manufacturing apharmaceutical product, kit or packaging system as disclosed herein; andb) marketing to healthcare providers the benefits of using thepharmaceutical product, kit or packaging system to deter counterfeiting,diversion or theft of the pharmaceutical product.

In certain embodiments, the invention is directed to a method forconducting a pharmaceutical business, comprising a) manufacturing apharmaceutical product, kit or packaging system as disclosed herein; andb) informing a law enforcement agency of the benefits of using thepharmaceutical product, kit or packaging system to deter counterfeiting,diversion or theft of the pharmaceutical product. This method mayfurther comprise providing the law enforcement agency with detectionequipment for analyzing the scent profile of the seized pharmaceuticalproduct to determine its authenticity, source, etc.

In certain embodiments, the invention is directed to a method forconducting a pharmaceutical business, comprising a) providing adistribution network for selling a pharmaceutical product or kitdisclosed herein; and b) providing instruction material to patients orphysicians for identifying the source of the pharmaceutical product orkit.

In certain embodiments, the invention is directed to a method forconducting a pharmaceutical business, comprising a) providing adistribution network for selling a pharmaceutical product or kit asdisclosed herein; and b) providing instruction material to a lawenforcement agency for identifying the source of the pharmaceuticalproduct or kit. This method may further comprise providing the lawenforcement agency with detection equipment for analyzing the scentprofile of the seized pharmaceutical product to determine itsauthenticity, source, etc.

In certain embodiments, the invention is directed to a method formarking a pharmaceutical product for identification, comprising:identifying a pharmaceutical product containing an active ingredientthat has been approved by a governmental agency for distribution andsale to the public; and imparting a scent to the pharmaceutical productin an amount that does not require reapproval by the governmental agencyof the pharmaceutical product reformulated to include the scent; whereinthe scent indicates the identity, source, or combination thereof of thepharmaceutical product.

In certain embodiments, the invention is directed to a method formarking a pharmaceutical product for identification, comprising:imparting a first scent to a pharmaceutical product and a second scentto a container for the pharmaceutical product; the first and secondscents providing an indication of the identity, source, or combinationthereof of the pharmaceutical product.

In certain embodiments, the invention is directed to a method formarking a pharmaceutical product for identification, comprising:imparting a first scent to a pharmaceutical product and a second scentto a packaging system for the pharmaceutical product; the first andsecond scent providing an indication of the identity, source, orcombination thereof of the pharmaceutical product.

In certain embodiments, the invention is directed to a method ofreducing diversion of a pharmaceutical formulation comprising impartinga scent to a pharmaceutical product in an amount which is below thehuman olfactory threshold; the scent being detectable by an olfactorydevice or a non-human mammal.

In certain embodiments, the invention is directed to a method ofreducing preventing pharmaceutical drug counterfeiting comprising;imparting a scent to a pharmaceutical product, a container for thepharmaceutical product, packaging for the pharmaceutical product, orcombination thereof; the scent imparted in an amount that isundetectable to the human sense of smell; the scent being detectable byan olfactory device or a non-human mammal such as, e.g., a canine.

In other embodiments, the invention is directed to a method of analyzingwhether a pharmaceutical product is counterfeit comprising testing apharmaceutical product with an unknown identity or source for thepresence of a scent that is the same as that of an authenticpharmaceutical product. In such embodiments, the absence of the scent isindicative of a counterfeit product and the presence of the scent isindicative of an authentic product.

Preferably, the present invention is useful in authenticating thepharmaceutical formulation, or preventing diversion of thepharmaceutical formulation, or tracking the distribution of thepharmaceutical formulation, or determining the source of thepharmaceutical formulation, or determining the specific batch of thepharmaceutical formulation, and/or determining the date of manufactureof the pharmaceutical formulation, or a combination thereof.

For purposes of the present invention, the term “marking a product foridentification” means associating a specific scent with a product sothat the authenticity, source, identity or other information about theproduct can be determined. The scent, particularly in the concentrationused, should be non-deleterious to the product, and preferably shouldnot already be associated with the product.

For purposes of the present invention the terms “aroma”, “scent”,“odor”, or “smell” may be used interchangeably.

For purposes of the present invention the terms “pharmaceuticalformulation” and “pharmaceutical product” may be used interchangeably.

The term “scent profile” for purposes of the present invention means theparticular scent or scents that are used to indicate the identity,source, or other information of the pharmaceutical product, container orpackage. The scent profile can be compared to a scent “fingerprint.” Forexample, the “scent profile” can be the particular peak or peaks whichare present when a composition of the present invention is tested withan olfactory measuring device.

The term “pharmaceutical formulation” or “pharmaceutical product” forpurposes of the present invention means a drug composition which hasreceived approval by a governmental authority (e.g., the Food and DrugAdministration of the United States) to be safe and efficacious in humansubjects.

The term “varying a scent” for purposes of the present invention meanschanging the scent used in the formulation, container, and/or packagingsystem. For example, varying a scent in the pharmaceutical formulationmeans that if one month the pharmaceutical formulation has, for example,an apple scent, then the next month the scent in the pharmaceuticalformulation is changed to, for example, an orange scent. Alternatively,“varying a scent” means changing the same scent, for example, varyingthe potency of an orange scent, from, e.g., month to month.

For purposes of the present invention the term “method for providing forthe indentification of” includes adding a marker to a pharmaceuticalproduct, container, and/or pharmaceutical packaging system in order toallow for the product, container and/or packaging system to beidentified for that marker.

For purposes of the present invention, the term “opioid agonist” isinterchangeable with the term “opioid” or “opioid analgesic” and includeboth a single opioid agonist and combinations of more than one opioidagonist, and also include the base of the opioid, mixedagonist-antagonists, partial agonists, pharmaceutically acceptable saltsthereof, stereoisomers thereof, ethers and esters thereof, and mixturesthereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a pharmaceutical container including a scent inaccordance with the present invention.

FIG. 2 depicts a pharmaceutical packaging system which includes a scentin accordance with the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides for a method to authenticate apharmaceutical formulation, and/or to identify its source ofdistribution or its site of manufacture, by imbuing the pharmaceuticalformulation, container or packaging material with a scent. Scent markerscan involve smell recognizable factors, perfumed or otherwise scentedmembers, “scratch and sniff” members, mixtures thereof and the like.

The scent for use in the present invention may be applied to, orincorporated into, the pharmaceutical formulation itself, or thecontainer apparatus (e.g., bottle) containing the pharmaceuticalformulation, or the box or other pharmaceutical packaging systemcontaining the container, and combinations thereof. Alternatively oradditionally, a scent releasant comprising a scent may be attached tothe container containing the pharmaceutical, or to the box or otherpharmaceutical packaging system, or to a combination thereof.

The inclusion of the scent of the present invention may be useful toprovide the user, dispenser and/or law enforcement personnel of thepharmaceutical formulation with confirmation that the formulation beingtested is the genuine pharmaceutical formulation from the correctsource. In certain preferred embodiments, the scent is useful to providelaw enforcement officials, border patrol police, and the like, with away to authenticate and/or verify the pharmaceutical formulation “in thefield”, or conversely to detect counterfeit formulations.

In certain embodiments, where the scent is included in thepharmaceutical formulation, the scent is preferably applied directly tothe pharmaceutical formulation via a standard coating process known inthe art, e.g., via any appropriate spraying technique known in the art.For example, once the pharmaceutical formulation is encapsulated ortableted, then the capsule or tablet may be further coated with a scentuseful for identifying the pharmaceutical formulation. In certain otherembodiments, the scent is incorporated into the formulation during thetableting or encapsulation process. For example, the scent may beincorporated into the formulation, e.g., during granulation, during thecoating process for bead formulations, during spheronization, appliedafter the aforementioned processes, in a combination of any of theaforementioned processes, and the like.

In certain preferred embodiments, when the scent is included in thepharmaceutical formulation, the scent is included in a coating on theformulation. In certain other embodiments, the scent is included in anintermediate coating of the pharmaceutical formulation and/or in a filmcoating on the final pharmaceutical formulation. For example, the scentmay be included in a coating such as Opadry® (Colorcon, Inc.).Alternatively, the scent can be included in e.g., a solution used in themanufacturing of the formulation, e.g., during granulation or spraycoating.

Preferably, when the scent is included in the pharmaceuticalformulation, the scent is in the pharmaceutical formulation in an amountof below about 0.1% of the final formulation. In preferred embodiments,the scent is included in an amount of less than 100 ppm, less than 50ppm, less than 25 ppm, less than 10 ppm or less than 5 ppm of the finalformulation. In certain preferred embodiments where the scent is addedto a pharmaceutical formulation which has already been approved by agovernmental agency that regulates pharmaceuticals (such as, forexample, the Food and Drug Administration of the United States ofAmerica), the scent is included in an amount (e.g., such as an allowableimpurity amount) which would not require a re-filing with, orre-approval by, the governmental agency of the pharmaceutical productthat has been reformulated to include the scent.

In certain embodiments, where the scent and the active ingredient of thepharmaceutical formulation are incompatible, the scent does not come incontact with the active ingredient of the pharmaceutical formulationduring the process of manufacturing the pharmaceutical formulationand/or in the final pharmaceutical formulation.

In certain embodiments, where the scent is included in thepharmaceutical formulation, the scent is in a sequestered form. Thescent can be sequestered using any know process such as, e.g., theprocess disclosed in PCT Publication WO 01/58451, the disclosure ofwhich is hereby incorporated by reference. In embodiments where thescent is sequestered, the scent is preferably not substantially releasedunless the integrity of the pharmaceutical formulation is compromised.The integrity of the pharmaceutical formulation can be compromised bycrushing the dosage form.

In certain embodiments, the present invention is directed to apharmaceutical formulation comprising an active agent, and a sequesteredscent indicating the identity or source of the pharmaceuticalformulation, wherein the scent is detectable to a human olfactory systemwhen the integrity of the pharmaceutical formulation is compromised.Alternatively, the present invention is directed to a pharmaceuticalformulation comprising an active agent and a sequestered scentindicating the identity or source of the pharmaceutical formulation,wherein the scent is undetectable to a human olfactory system when theintegrity of the pharmaceutical formulation is compromised, but isdetectable either by a non-human animal (e.g., a canine) or by anolfactory measuring device when the integrity of the pharmaceuticalformulation is compromised.

In certain preferred embodiments, when the scent is in sequestered form,the scent is included in multiparticulates, wherein themultiparticulates are individually coated with a material thatsubstantially prevents release of the scent until the muliparticulatesare dissolved or crushed. The multiparticulates may be incorporated intoa pharmaceutical formulation with an active agent, e.g., into a tabletor a capsule.

In certain other embodiments, the scent in sequestered form is dispersedin a matrix comprising a material which substantially prevents therelease of the scent. The matrix may be incorporated into apharmaceutical formulation with an active agent, e.g., into a tablet ora capsule.

Sequestering materials for use in accordance with the present inventioninclude those materials disclosed, among other places, in PCTPublication WO 01/58451. In certain preferred embodiments, a scent insequestered form may be prepared by combining the scent with one or morepharmaceutically acceptable hydrophobic materials. For example,particles comprising the scent may be coated with a hydrophobic coatingthat sequesters the scent. Another example would be a scent that isdispersed in a matrix that sequesters the scent. In other embodiments,the scent can be sequestered in a matrix, with the sequestrationaugmented with the use of a coating over the matrix.

In certain embodiments directed to a sequestered scent, compromising theintegrity of the formulation can provide a “burst” effect. This canfacilitate the detection of the scent, e.g., by a human olfactorysystem, a non-human mammalian animal, or an olfactory measuring device,or a combination thereof. This may also provide a pharmaceuticalformulation that hinders counterfeiting since it would be more difficultfor a counterfeiter to recreate the “burst” effect of the formulation.In other embodiments, the scent is released from a pharmaceuticalformulation in a controlled, prolonged, and/or gradual release.

In certain further embodiments, where the scent is included in thecontainer containing the pharmaceutical formulation, the scent may beincorporated into the container during the manufacturing process of thecontainer, and/or the scent may be applied to the inner and/or outerportions of the container. According to this embodiment, the containermay take any appropriate form. Preferably, the container has a closureportion that is integral to the container, or that can be removable fromthe container. In certain preferred embodiments, the container is abottle having a neck including an open top, and a closure portion thatis rotatably affixed (e.g., a screw-on or child-proof cap) onto the neckof the bottle. In certain embodiments, the scent is release when thecontainer is opened.

In certain embodiments, the wall of the container comprises a substrate(e.g., nylon) that has been impregnated with a scent, which can beprepared by immersing the container in an aqueous solution containingthe scent for a time period sufficient to allow the scent to be absorbedby the substrate. The aroma component can subsequently be released bysimple handling of the bottle. Examples of such odor-impregnatingtechniques are disclosed, among other places, in U.S. Pat. Nos.3,871,334 and 4,674,444, the disclosures of which are herebyincorporated by reference. In another embodiment, the scent-producingcomponent can be added to, and uniformly distributed throughout, acontainer (e.g., a polyurethane container) during the initialmanufacture of the container.

In certain preferred embodiments, the scent is released from thecontainer through the use of a scent releasant means, which preferablycontains at least one scent useful as a marker according to the presentinvention. The scent releasant may be, for example and withoutlimitation, a scented adhesive, a scent patch, a scent burst film, ascent dispensing tab, a scent containing capsule, a microencapsulatedscent, a film of microencapsulated scent, or a combination thereof.

In certain embodiments, the scent releasant comprises an absorbentsubstrate in which the scent or scent source is stored in a volatilecomposition to be released when the container is opened. The absorbentpreferably acts as a reservoir to retain the volatile scent composition,and releases a portion of the volatile scent composition each time thereservoir is exposed upon opening of the container. In certain preferredembodiments, the scent is released by tearing or stretching theabsorbant substrate to release the scent.

In certain embodiments, the scent-containing substrate is in the form ofan aroma strip which is covered by a re-sealable film, such that eachtime the film is pulled back from the strip (e.g., by opening thecontainer), the strip releases the volatile scent, and scent release issubsequently stopped or minimized by re-applying the film to the strip.In certain embodiments, the scent is released by tearing or stretchingthe film until the film becomes perforated. Preferably the film hasassociated, re-sealable, pressure sensitive adhesive to ensure that thestrip is resealed upon each closure of the container.

In certain embodiments the scent releasant can be a scent-dispensing tabthat may be applied to the container or included in the container. Forexample, the tab may be in the form of a sac constituted by a basehaving a perforated dome marginally secured thereto to define a ventedchamber occupied by an absorbent pad saturated by a liquid scent. Thetab preferably has a layer of a pressure-sensitive adhesive allowingattachment of the tab to the container containing the pharmaceuticalformulation.

In certain preferred embodiments, the scent releasant is a layer ofmicroencapsulated scent material containing scent microcapsules, and issecured to at least one of the top or closure portion of the container.When the closure portion is rotated on the neck of the container forremoval from the top to open the container so that the pharmaceuticalproduct is dispensed therefrom, at least some of the aroma capsules areruptured and the scent is released.

Microencapsulation is a process in which very thin coatings of inertnatural or synthetic polymeric materials are deposited around microsizedparticles of solids, droplets of liquids, or gas. Products formed areknown as microcapsules. Microcapsules typically consist of two majorparts (i.e., the inner part and the outer part). The inner part is thecore material comprised of one or more active ingredients. In accordancewith the present invention, the active ingredient for encapsulation isone or more of the scents described herein. These active ingredients maybe in the form of solids, liquids, or gases. The outer part is thecoating material, which is preferably a high molecular weight polymer ora combination of such polymers. The coating material can be chosen froma number of natural and synthetic polymers. The coating materialpreferably is non-reactive with the core material, and is preferablybiodegradable and nontoxic. Other components such as, for example,surfactants and plasticizers, may also be added to microcapsules.

The encapsulation may provide for the enhancement of the stability ofthe core material including the scent. For example, the encapsulation ofa scent preferably protects the scent against atmospheric deterioration.

Preferably, the scent releasant described herein is in contact with thecontainer. Preferably, the scent releasant releases a unique scent thatcan be associated with the pharmaceutical formulation contained in thecontainer.

In certain embodiments, a label is provided on the outside of thecontainer. The label may be applied to the outside of the container byan adhesive. In certain embodiments, the adhesive may contain the scent,the scent may be applied over the label, the label itself may containthe scent, or a combination of the aforementioned may be used. The labelmay further include some other identifying feature for the drug.Further, the label may comprise a package insert that provides detailsabout the pharmaceutical formulation contained in the container and isapplied to the container by an adhesive. Additionally, the scent area ofthe label or of the container may also be covered with a peel-off typecover to preserve the freshness of the scent during shipping andstorage.

The label may simply be coated with a liquid solution containingscent-producing elements and then sealed with a protective coating. Onemethod of applying scent producing elements to a label utilizes themethod commercialized by Sandy Alexander, Inc., of Clifton, N.J., whichemploys a press varnish that may be directly applied to printing pressesto enable the combination of high-quality color printing and scentingwithin an in-line operation. This process produces a label with anintegrated scent area, and permits labels to be manufactured without anadditional step. According to this process, the intensity of the scentcan be controlled and the image printed on the sheet material does nothave to be distorted or broken up to release the scent. Additionally,this process allows application in defined areas and can allow formultiple scents on a single sheet of material. This scent release isactivatible a number of times, and requires no special paper orsubstrate so conventional substrates for labels are suitable.

In certain embodiments, the headspace of the container containing thepharmaceutical formulation is filled with a scent or aroma so that uponopening the container, the person opening the container can identify thepharmaceutical contained therein by the scent or aroma releasedtherefrom.

The container having a scented headspace portion can be prepared bytechniques known in the food packaging art. Systems for aromatizingheadspace of a food package that may be used in accordance with thepresent invention are disclosed, among other places, in European PatentNo. 0 706 944 and U.S. Pat. No. 5,885,640, the disclosures of which arehereby incorporated by reference in their entireties. Another techniqueincludes providing a pharmaceutical container which defines a cavity forcontaining a pharmaceutical formulation; inserting a pharmaceuticalformulation into the cavity; inserting a liquid mixture of apharmaceutically acceptable scent composition liquid carrier into aportion of the container separate and apart from the cavity whichcontains the pharmaceutical formulation; removing the liquid carrierfrom the scent composition, preferably by evaporating the carrier, whileleaving the scent composition preferably in a form of a residue,preferably comprising a solidified form, so that the scent is releasedfrom the container upon opening the container; and covering and sealingthe container part with a cover part so that the pharmaceutical andscent composition are sealed and contained within the package separateand apart one from the other within separate package cavities and sothat the cover part is removable and so that when the cover part isremoved, the separate cavities are opened to the atmosphere releasingthe scent.

In carrying out the process with a liquid carrier, so that removal ofthe carrier may be effected, the carrier is preferably selected fromsolvents having a boiling point at or lower than 100° C. at standardatmospheric pressure, which enables readily carrying out evaporation orvolatilization of the carrier. Such solvents can be aqueous or organicand include, for example and without limitation, water, ethanol,methylformate, ethylformate, propanol, hexane, mixtures thereof, and thelike. In preferred embodiments, the liquid solvent carrier is removed bypulling a vacuum so the solvent evaporates or vaporizes. Preferably theresidue that remains is not visually perceptible, but is in aconcentration or amount effective to provide the intended olfactoryeffect upon opening the package. In certain embodiments, the scentcomposition may also be present in an aerosol form or gaseous formrather than only as a residue.

Preferably, the scent composition is in an amount such that it iseffectively available for olfactory response when the cover part ispeeled off the container. In certain preferred embodiments, the coverpart may be a web or sheet, or other known materials suitable forcovering and sealing package bottles containing pharmaceuticalformulations, such that the cover part is peelable and sealed to form apackaged body.

In certain embodiments, the amount of scent to be applied and/orincorporated into a container and/or pharmaceutical formulation willdepend upon the smell intensity of the scent concentrate. Preferably theamount used is a sufficient amount to impart the desired scent(detectable or undetectable to humans) to the container such that thescent will be retained and not dissipate under normal storage. The scentpreferably provides for the identification of the pharmaceuticalformulation and/or source of the pharmaceutical formulation contained inthe container or the packaging system. In certain embodiments, the scentprovides for the ability to determine the manufacturing site of thepharmaceutical formulation, the specific batch of the pharmaceuticalformulation, the date on which the pharmaceutical product wasmanufactured, or a combination thereof. In certain embodiments, thescent included in the pharmaceutical formulation and/or packaging systemmay be varied in order to prevent counterfeiters from producing thepharmaceutical formulations and/or packaging systems with the samescent. For example, the scent can be varied for every new pharmaceuticalbatch prepared, or every few months, or every one or two years, etc.

In certain embodiments, the container including the pharmaceuticalformulation can be placed within a packaging system such as, e.g., abox. In certain embodiments, the packaging system includes a scentreleasant as described herein. For example, when the packaging system isa box, the box preferably includes at least one flap defining a closure.The scent releasant can be included in the adhesive utilized for sealingthe flap of the box or for securing indicia, e.g., a patient packageinsert, onto the box. The scent included in the adhesive preferablyprovides the ability to determine the manufacturing site of thepharmaceutical formulation, the specific batch of the pharmaceuticalformulation, the date on which the pharmaceutical product wasmanufactured, or a combination thereof. Preferably, the scent iscontinuously released from the adhesive.

In another embodiment, the scent releasant can be a scent burst filmdisposed over the flap of the box. Preferably, the scent burst film isplaced between two flaps of a closable package system, wherein the flapsare in overlapping opposing relationship and the scent burst film can beadhered between opposing overlapping flaps. In a preferred embodiment,the scent burst film includes a supporting base adhered to at least oneflap of a package, a layer bonded to the outside face of the supportingbase, the layer comprising, e.g., a vinyl plastisol resin containing ascent, and a flexible, continuous, smooth cover sheet covering the layerwhereby the scent is retained for extended periods of time. The coversheet is preferably adhered to the second overlapping flap of thepackage. Upon removal of the cover sheet (e.g., by removal of one of theoverlapping flaps), the scent becomes immediately available and isgradually released.

In certain other embodiments, the scent releasant of the packagingsystem of the present invention is a separate scent compartment attachedto the flap of the package. The compartment suitable for containing ascent is sealed with a removable cover. The scent is released when theremovable cover of the compartment is removed.

In another embodiment, the scent compartment is a separate cavity formedinto the flap, the cavity being sealed with a removable cover. The scentis releasable when the removable cover is removed.

In another embodiment, the scent releasant is a scent dispensing tabwrapped in a hermetically sealed foil package that prevents emission ofthe scent until the foil package is ruptured, wherein the foil packagingsystem can be adapted to adhere to at least one flap of the package orto the container described above. The scent-dispensing tab can bedisposed on the interior or exterior of the flap (or container orcontainer closure). The scent-dispensing tab can be a pad or wicksaturated with a concentrated liquid scent that retains and releases thescent contained therein.

In another embodiment, the scent releasant can be an adhesive label onthe container described above or the packaging system described above,the label being coated on its outer face with a thin film ofmicroencapsulated scent, wherein the microencapsulated scent is coveredby a protective coating whereby the scent is released by scratching offthe protective coating, thereby disrupting the capsules containing thescent (e.g., such as a “scratch and sniff” formulation). In certainembodiments, the scent releasant of the packaging system or containerapparatus is a scent-containing capsule breakable by hand pressure,wherein the capsule is secured to the exterior of the flap.

In certain preferred embodiments of the present invention, the scent isin an amount or concentration that is undetectable by the human sense ofsmell, but is detectable by the use of an electronic olfactory measuringdevice. The olfactory measuring device may be used, for example, by theuser of the pharmaceutical product (e.g., the patient), the dispenser ofpharmaceutical product, a person involved in the chain of distributionof the product, a law enforcement official, or the manufacturer of theproduct.

Suitable olfactory measuring devices include those described in, forexample, U.S. Pat. Nos. 5,675,070 and 5,177,994, and those manufacturedby Neotronics of Hertfordshire, Great Britain; ALPHA M.O.S., Inc. ofDeMotte, Ind.; and Aromascan Inc. of Hollis, N.H.

In certain embodiments, the olfactory measuring device is known as anElectronic Nose. See H. T. Nagle, S. Schiffman and R. Guitierrez-Osuna,“The How and Why of Electronic Noses”, IEEE Spectrum, pg. 22-33,September 1998. An electronic nose provides a recognizable visual imagein N-dimensional space (where N equals the number of sensors) ofspecific vapor mixtures (fragrances) containing possibly hundreds ofdifferent chemical species. An electronic nose is designed to quantifyand characterize scents. Sensors are selected for their chemicalaffinities, and chemi-sorbing polymer films are commonly used for thispurpose. Many sensors can be used, and a serial polling of each sensorreading produces a histogram of sensor outputs, which comprises theolfactory response of the electronic nose. Certain “artificial noses”that may be used in accordance with the present invention includetransducer arrays, the collective output signal of which correlates tothe existence of a compound having a certain odor. Such artificial nosesare described, among other places, in U.S. Pat. Nos. 4,818,348;4,844,535; 5,071,770; 5,541,851; and 5,928,609. Electronic nosesdescribed in J. Yinon, Analytical Chemistry, “Detection of Explosives byElectronic Noses” (2003), may also be used in accordance with thepresent invention.

In certain embodiments, a method, apparatus and system as described inPCT Publication WO 02/22075 A2 may be used to compare the odorcharacters of liquid and gaseous fragrance materials based on acomparison of the optical absorption spectrum in the UV to the near IRassociated therewith.

In certain embodiments, the olfactory measuring device is, or comprises,a gas chromatography device. See Robert L. Grobe, “Modern Practice ofGas Chromatography”, John Wiley & Sons, copyright 1985 Part 1, Chapter2, Theory of Gas Chromatography, pp. 50-114, to Separate the vapor intoits individual chemical components and to obtain a chromatographic“scent profile”. Common GC systems utilize long capillary columns manymeters in length, and although analysis times may be long, they tend tobe accurate and precise. A recent development has been the use ofdirectly heated short chromatography columns, cooled sample traps, andfocused surface acoustic wave (SAW) interferometric vapor detectors.See, e.g., U.S. Pat. No. 5,289,715. The SAW detector produces a variablefrequency in response to analytes condensing upon and evaporating fromthe surface of a temperature controlled piezoelectric crystal.

In certain alternative embodiments, the olfactory measuring deviceincludes JR, NMR and mass spectrometry devices.

In certain embodiments, the olfactory device is a handheld olfactorydevice, which is easily useable, e.g., by law enforcement individualssuch as border police. Preferably, the olfactory device is designed toauthenticate a particular pharmaceutical formulation based on detectionof a scent (e.g., a covert scent) included in the pharmaceuticalformulation and/or the pharmaceutical packaging system, and is designedto provide a simple “yes” or “no” answer. In certain preferredembodiments, the olfactory device is self-destructing when the deviceitself is tampered with in order to avoid the replication or tamperingof the olfactory device or any software program installed in theolfactory device.

Scents for use in the present invention can be selected from anyappropriate scents known in the art including, for example, any scentfrom the group consisting of volatile oils, synthetic flavor oils,flavoring aromatics, natural flavor oils, flavoring liquid oleoresins,flower extracts, fruit extracts, combinations thereof, and the like. Incertain embodiments, the scent can be selected from the group consistingof aldehydes and esters such as benzaldehyde (cherry or almond), citral,i.e., alphacitral (lemon or lime), neral, i.e., beta-citral (lemon orlime), decanal (orange or lemon), aldehyde C-8 (citrus fruits), aldehydeC-9 (citrus fruits), aldehyde C-12 (citrus fruits), tolyl aldehyde(cherry or almond), 2-6-dimethyloctanal (green fruit), 2-dodecenal(citrus or mandarin) and mixtures thereof, and the like. Other scentsthat may be useful include, for example and without limitation, anise,apple, arnica, balm mint, banana, basil, black pine, caraway, carnation,chamomile, cherry, Chinese cedar wood, chocolate, cinnamon, coconut,coffee, cypress, dill weed, eucalyptus, fir, fleurier, florogenia,forest ground, fresh baked bread, ginger bread, green apple, green bean,green spruce, hay flower, hazel, honey, hyacinth, incense, jacilia,jasmine, juniper, keymi, lavender, leather, lemon, lilac, lotus,mandarin, mango, maracuja, marjoram, May-flower, menthol, mixed alpineherbs, mugol, northern birch, ocean breeze, orange, orchid, ozone pine,peach, pear, petunias, pine, pinewood, pink pepper, pizza, plum, rose,raspberry, rosemary, sandalwood, sea breeze, Siberian spruce, spring,spruce pine, strawberry, thyme, tobacco, tomato, valerian, vanilla,violet, waffle, wild woodberry, mixtures thereof, and the like. Incertain embodiments a musk scent may be used.

In certain preferred embodiments, the scent is “generally recognized assafe” by the Flavor and Extract Manufacturer's Association. In certainpreferred embodiments, the scent is, for example and without limitation,trans-anethole (1-methoxy-4-propenylbenzene)-anise; benzaldehyde(benzoic aldehyde)—bitter almond; butyl isobutyrate (n-butyl 2, methylpropanoate)—pineapple; cinnamaldehyde (3-phenylpropenal)—cinnamon;citral (2-trans-3,7-dimenthyl-2,6-octadiene-1-al)—citrus; menthol(1-methyl-4-isopropylcyclohexane-3-ol)—menthol; and alpha-pinene(2,6,6-trimethylbicyclo-(3,1,1)-2-heptene)—pine.

In certain other embodiments, the scent is selected from aliphatic fattyacids with short chains of two to six carbon atoms, such as acetic acid,propionic acid, isobutyric acid, isovaleric acid and isocaproic acid;ketones, such as α-ionone and 2-piperidone; aldehydes, such as4-hydroxy-3-methoxy benzaldehyde; amines such as triethylamine; o- andp-hydroxy benzoic acids and their esters, in particular p-hydroxybenzoic acid, p-hydroxymethyl benzoate, p-hydroxyethyl benzoate andp-hydroxypropyl benzoate, and methyl salicylate (orthohydroxybenzoate);combinations thereof and the like.

Additional lists of odorous molecules identified by their molecularweight and their saturation vapor tension can be found in standard workssuch as “Handbook of Organic Chemistry”, for example, and in specializedworks in the field of olfaction, psychophysiology and animal behaviorsuch as, for example, the series of works entitled “Chemical Signals inVertebrates” Volumes 1-9, Kluwer Academic Publishers, 1977-2001.

In certain embodiments, Perfluorocarbon Tracer (PFT) technology asdescribed in U.S. Pat. No. 5,409,839, the disclosure of which is herebyincorporated by reference, is used in accordance with the presentinvention. In such embodiments, the pharmaceutical product, container,and/or packaging system is includes a PFT that gives off a detectabletracer (e.g., vapor or scent), which can be detected by humans, anon-human, and/or an olfactory measuring device. Such PFT's include, forexample and without limitation, perfluorocycloalkanes such asperfluorodimethylcyclobutane (PDCB), perfluoromethylcyclohexane (PMCH),and perfluorodimethylcyclohexane (PDCH); perfluoroaromatics such ashexafluorobenzene (HUB), octafluorotoluene (OFT), decafluorobinphenyl(DFBP), decafluoroxylene (DFX), octafluoronaphthalene (OFN), andpentafluoropyridene (PM, perfluoroalkanes such as perfluorohexane (PFH),perfluoropentane (PFPT), and perfluorooctane (PFO), andperfluorocycloalkenes such as decafluorocyclohexene (DFCH) andoctafluorocyclopentene (OFCP), pf-methylcyclopentane (PMCP);pf-1,2-dimethylcyclohexane (o-PDCH¹); pf-1,3-dimethylcyclohexane(m-PDCH¹); pf-1,4-dimethylcyclohexane (p-PDCH¹);pf-trimethylcyclohexanes (PTCH); and combinations thereof. Certainpreferred PFT's are PMCH, PMCP, o-PDCH¹, m-PDCH¹, p-PDCH¹ and PTCH.

In certain embodiments, the scent for use in the present invention is ina quantity that is perceivable by the human sense of smell. In certainalternate embodiments, in order to prevent counterfeiting of the aromas,and to provide a covert “scent profile” of the pharmaceutical product,the scent is in a quantity which is difficult to perceive or notperceivable by the human sense of smell, but which can be detected byother means.

For example, in certain embodiments the scent for use in the presentinvention is in a quantity that is physiologically difficult toperceive, preferably physiologically unperceivable, by the human senseof smell, but is in an amount that is sufficient either to be perceivedby a non-human mammal (e.g., a canine) or detected by an olfactorymeasuring device capable of identifying the odor emitted. Preferably,the scent is known to be capable of being detected by a non-human mammalor by an olfactory measuring device (as disclosed above) at extremelylow thresholds.

The sense of smell is much better developed in certain mammals, whethernaturally or after training, than in human beings. By use of their senseof smell, these mammals can identify the identity or origin of evenextremely tenuous or faint odors. In certain embodiments, it issufficient to affix to the pharmaceutical product a specific scent knownto be undetectable by the human sense of smell, but detectable by agiven animal or olfactory measuring device. Dogs may be especiallyuseful in accordance with carrying out the present invention, since adog's sense of smell is up to a million times more sensitive than thatof a human. In addition, there are certain odors that are particularlyoffensive to dogs, such as citrus smells (e.g., lemon, lime, andorange), spicy smells (e.g., red pepper) and citronella. Therefore, incertain embodiments, one or more of these scents are preferred, sincethey be more detectable by canines

In certain preferred embodiments, the amount of scent used is in anextremely low concentration, and in particular, is in a concentration sothat one skilled in the art may easily affix a carrier containing ascent to the object to be marked such that the carrier comprising thescent is imperceptible to the human eye.

In certain embodiments, the present invention is further directed to amethod of varying or changing the scent for use in the presentinvention, preferably depending on the particular time and/or place thatthe pharmaceutical formulation was manufactured, bottled, or packaged.For example, if the pharmaceutical formulation was manufactured on aMonday, then the scent could be one specific odor or combination ofodors (e.g., cherry, apple, combination thereof) giving a certain “scentprofile” or “scent fingerprint”; if the pharmaceutical formulation wasmanufactured on a Tuesday, then the scent could be a different specificodor or combination of odors (e.g., chocolate, banana, combinationthereof). In a preferred embodiment, the scent can be varied dependingon the lot or batch number of the pharmaceutical formulation. Forexample, the scent incorporated into the pharmaceutical formulation; thecontainer containing the pharmaceutical formulation; the box or otherpharmaceutical packaging system containing the bottle or apparatus;combinations thereof; and the like, in one lot can be one odor orcombination of odors (e.g., cherry, apple, combination thereof), whileanother lot can be another odor or combination of odors (e.g.,chocolate, banana, combination thereof).

In certain preferred embodiments the present invention is furtherdirected to a method of preventing diversion of a pharmaceuticalformulation. For example, the inclusion of the scent in accordance withthe present invention could be used to determine the source (e.g., themanufacturing plant or pharmaceutical distribution facility) of thepharmaceutical formulation. In view of the fact that the manufacturingand packaging of a pharmaceutical product can be carried out indifferent parts of a country and/or in multiple countries, the inclusionof different scents in the pharmaceutical product could provide theinformation necessary to indicate, e.g., which manufacturing facilitywas the source for the pharmaceutical. The inclusion of different scentsin a pharmaceutical product could serve to indicate whether a producthas been diverted from a proper consumer, client, or customer, to animproper consumer, client, or customer.

In certain preferred embodiments, the packaging system, container, orpharmaceutical formulation of the present invention can further includea visual indicator. A visual indicator can be, for example, a certainink, dye, phosphorescent material, hologram, watermark, micro-replicatedpattern, or a combination thereof.

In certain embodiments, a marker composed of a low molecular weighthapten may be covalently bound to an ingredient in the pharmaceuticalformulation, a component in the container or pharmaceutical package, orcombination thereof. Such markers are described, for example, in PCTPublication WO 95/06249, the disclosure of which is hereby incorporatedby reference. In certain embodiments wherein a hapten is included, themarker can be produced by first covalently binding a hapten to afunctional monomer, and then polymerizing the hapten-monomer compound toform a polymer having covalently-bound hapten. Thereafter, the polymercan be incorporated into the pharmaceutical dosage form, container,and/or the pharmaceutical package. The presence of the hapten marker canbe detected as described in PCT Publication WO 95/06249.

The methods of the present invention can be used in accordance with anypharmaceutical formulations known in the art, and particularly thosesusceptible to theft, diversion, counterfeiting, and/or misuse or abuse.In certain preferred embodiments, the pharmaceutical formulation of thepresent invention comprises an opioid analgesic. In a non-limitingembodiment, an opioid analgesic useful in the pharmaceutical formulationcan be selected from alfentanil, allylprodine, alphaprodine,anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol,clonitazene, codeine, desomorphine, dextromoramide, dezocine,diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol,dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone,eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine,etonitazene, etorphine, dihydroetorphine, fentanyl, a fentanylderivative, heroin, hydrocodone, hydromorphone, hydroxypethidine,isomethadone, ketobemidone, levorphanol, levophenacylmorphan,lofentanil, meperidine, meptazinol, metazocine, methadone, metopon,morphine, myrophine, narceine, nicomorphine, norlevorphanol,normethadone, nalorphine, nalbuphene, normorphine, norpipanone, opium,oxycodone, oxymorphone, papavereturn, pentazocine, phenadoxone,phenomorphan, phenazocine, phenoperidine, piminodine, piritramide,propheptazine, promedol, properidine, propoxyphene, sufentanil,tilidine, tramadol, mixtures of any of the foregoing, salts of any ofthe foregoing, and the Like. In certain embodiments, the amount of theopioid analgesic in the dosage form of the pharmaceutical formulationmay be from about 75 ng to about 750 mg. The opioid analgesic may be inimmediate release or controlled release form.

In certain preferred embodiments, the opioid analgesic is selected fromthe group consisting of hydrocodone, morphine, hydromorphone, oxycodone,codeine, levorphanol, meperidine, methadone, oxymorphone, buprenorphine,fentanyl, a fentanyl derivative, dipipanone, heroin, tramadol,etorphine, dihydroetorphine, butorphanol, levorphanol, salts thereof andmixtures thereof. In certain preferred embodiments, the opioid analgesicis oxycodone or hydrocodone or salts thereof.

Certain other drugs which are useful in accordance with the presentinvention, include for example and without limitation, alimentary drugs;anti-infectives (e.g., antibiotics; anti-fungals; anti-virals such asanti-HIV/AIDS and anti-herpes; and anti-malarials); cardiovascular drugs(e.g., ace inhibitors; and cholesterol lower drugs such as the statins(e.g., Lipitor®)); CNS drugs (e.g., SSRIs such as Zoloft®, Prozac®,Effexor®, Lexapro®; anti-anxiolytics such as benzodiazepines; stimulantssuch as Ritalin®); dermatological drugs; genito-urinary drugs; hormones(e.g., anabolic steroids; growth hormone; and estrogen); life styledrugs (e.g., drugs for treating erectile dysfunction such as Viagra®,Levitra®; drugs for treating hair loss such as Propecia®);musculo-skeletal drugs; and respiratory drugs.

The following descriptions are for exemplification purposes only andexamples are not meant to limit the invention in any manner.

Referring to the drawings, and initially to FIG. 1, a conventionalpharmaceutical container is illustrated which has a threaded neck 11 towhich a cap 12 can be threadedly engaged to keep the neck sealed.Threaded neck 11 has a spiral thread formed on it which engages one ormore complementary threads formed on the inner surface of the cap 12,Additionally, neck 11 has an annular ring or flange 13 projecting fromit which engages a complementary inwardly projecting ring on the bottomof cap 12 that is secured to the base of the cap in a well known manner.In accordance with this embodiment, a layer of material 14 containingmicroencapsulated aroma is applied to the underside of flange 13 on neck11. Preferably, the microencapsulated material 14 is applied to flange13 as a slurry and allowed to dry. When the bottle is opened by turningthe cap the microcapsules burst and release the aroma.

FIG. 2 is a cross-sectional view of overlapping flaps of apharmaceutical packaging system which includes the base flap 21, face 21a of which is overcoated with layer 22 comprising a scent and adhesive,and flap 23, which contacts surface 22 a. When flap 23 is removed, itcauses the scent in layer 22 to be released.

Example 1

In this prophetic example, hydrocodone sustained release tablets areproduced with the formula set forth in Table 1 below:

TABLE 1 Ingredients Amt/Unit (mg) Amount/Batch (gm) HydrocodoneBitartrate 15.0 150.0 Spray Dried Lactose 56.0 560.0 Povidone 4.0 40.0Eudragit RS30D (solids) 10.0 100.0 Triacetin 2.0 20.0 Stearyl Alcohol20.0 200.0 Talc 2.0 20.0 Magnesium Stearate 1.0 10.0 Total 110.0 1100.0

According to the following procedure:

-   1. Retardant dispersion: Blend Eudragit RS30D and Triacetin using a    lightning mixer.-   2. Melt Stearyl Alcohol.-   3. Spray retardant dispersion onto Hydrocodone Bitartrate, Spray    Dried Lactose, and Povidone using a fluid bed granulator.-   4. Dry batch on a stainless steel tray for 15 minutes, or till    constant weight.-   5. Incorporate the melted Stearyl Alcohol into the batch using a    Hobart mixer.-   6. Dry waxed granulation on a stainless steel tray for 30 minutes,    or temperature of granulation reaches 35° C. or less.-   7. Mill the cooled granulation through a CoMil.-   8. Lubricate the granulation with talc and magnesium stearate using    a Hobart Mixer.-   9. Compress the granulation into tablets using a tablet press.

The tablets are then coated with an aqueous film coating which isprepared by, e.g., dispersing 5.0 gm Opadry Purple YS-1-10371-A (perbatch) and an amount of decanal in purified water and applying it to thetablet cores. The amount of decanal can be in an amount above the humanthreshold, or below the human threshold, but in an amount to bedetectable by an electronic nose. The amount of decanal to obtain thedesired threshold can be determined by one skilled in the art, e.g., byreference to page 51 of M. Devos, et al., Standardized Human OlfactoryThresholds, 1990.

Example 2 Scented Sequestered Naltrexone

In this prophetic example, the opioid antagonist naltrexone HCl isformulated as a melt extruded multiparticulates (hereinafter “MEMs”) toproduce a sequestered product. The formula is listed in the table below.

TABLE 2 Amt/unit Amt/batch Ingredient (mg) (kg) Naltrexone HCl 2.0 0.10Eudragit RSPO 88.0 4.40 Stearyl Alcohol 15.0 0.75 Stearic Acid 15.0 0.75Butylated Hydroxytoluene (BHT) 1.0 0.05 Total 121.0 6.05

The naltrexone HCl formulation of Example 1 is prepared using thefollowing process:

Process

1. Milling: Pass the stearyl alcohol flakes through an oscillating millequipped with a 16 mesh screen to achieve a powder that is easilyblendable.

2. Blending: Mix Naltrexone HCl, Eudragit RSPO, milled Stearyl Alcohol,Stearic Acid and BHT in a twin shell blender.

3. Extruding: Continuously feed the blended material from Step 2 into atwin screw extruder and collect extruded (Leistritz ZSE-27) at a rateranging from 1.7 kg/hr to 2.6 kg/hr. Extrude the blend at a barreltemperature range of 75° C. and 100° C. into strands approximately 1 mmin diameter. Collect the extruded strands on a conveyor.4. Coolin: Allow the strands to cool on the conveyor.5. Pelletizing: Cut the cooled strands into pellets approximately 1 mmin length using a Pelletizer.6. Screening: Screen the pellets through a vibratory separator using a16 TBC mesh and a 26 TEC mesh screen. Collect the material retained onthe 26 TBC mesh screen as desired product.7. Encapsulating: Fill the screened pellets into hard gelatin capsulesat a target weight of 121 mg.

An amount of benzaldehyde is included in the above process in theblending and/or the extruding step.

The scented MEMs are then coated with a 25% coating of acrylic polymeras follows:

Table 2A Coated Pellet Formula for 25% Weight Gain Amt/unit Amt/batchIngredient (mg) (kg) Scented Naltrexone HCl 121.0 0.50 Pellets EudragitRS30D (solids) 30.25 0.125 TriEthyl Citrate 6.05 0.025 Cab-O-Sil 1.50.0062 Opadry Pink 6.0 0.025 Total 164.8 0.68

The coating is prepared according to the following process:

Process

1. Functional Coating Dispersion: Mix Eudragit RS 30D with triethylcitrate to plasticize for 15 minutes. Disperse Cab-O-Sil in enough waterto achieve a total of 20% w/w solids dispersion. Add the Cab-O-Sildispersion to the Eudragit mixture.

2. Color Coating Dispersion: Mix Opadry with water to get a 10% w/wdispersion.

3. Functional Coating: Spray the Eudragit dispersion onto the Naltrexonepellets prepared above at 700 g scale using a fluid bed processor(GPCG-1) with the following parameter guidelines:

-   -   Air Speed: 8.5 to 9.5 m/s    -   Inlet Air Temperature: 35° C.    -   Dispersion Spray Rate: 14 g/min

Samples were taken at when the theoretical amount of dispersion wassprayed for 5%, 10%, 15%, 20%, and 25% weight gain.

4. Color Coating: Upon completion of the functional coating, sprayOpadry dispersion onto the coated pellets using the following parameterguidelines:

-   -   Air Speed: 8.5 m/s    -   Inlet Air Temperature: 35-45° C.    -   Dispersion Spray Rate: 8.5 g/min        5. Screening: Screen the pellets through a 14 US mesh screen and        a 20 US mesh screen. Collect the material retained on the 20 US        mesh screen as desired product.        6. Curing: Place the screened pellets and samples in an oven at        45° C. for 24 hours.

Upon crushing with a mortar and pestel, it is expected that a “burst” ofscent will be released which can facilitate the detection of the scent,e.g., by a human olfactory sytem, a non-human mammalian animal, or anolfactory measuring device, or a combination thereof. The amount ofdecanal to obtain the desired threshold can be determined by one skilledin the art, e.g., by reference to page 28 of M. Devos, et al.,Standardized Human Olfactory Thresholds, 1990.

In an alternate embodiment, a second scent, e.g. decanal, can beincluded in the color coating of step 4 in a similar manner as inExample 1.

While the invention herein disclosed has been described by means ofspecific embodiments and applications thereof, numerous modificationsand variations could be made thereto by those skilled in the art withoutdeparting from the spirit and scope of the present invention. Suchmodifications are understood to be within the scope of the appendedclaims.

What is claimed is:
 1. A pharmaceutical formulation comprising a drugand an imparted volatile scent, wherein the scent comprises less than100 ppm of the dosage form, provides an olfactory effect which isphysiologically unperceivable by humans, is detectable by a non-humananimal or an electronic olfactory measuring device, excludesperfluorocarbon tracers, and indicates when and/or where thepharmaceutical formulation was manufactured, bottled or packaged, andthe pharmaceutical formulation is a tablet or a capsule.
 2. Thepharmaceutical formulation of claim 1, wherein the amount of the scentis detectable by the electronic olfactory measuring device.
 3. Thepharmaceutical formulation of claim 1, wherein the scent indicates wherethe pharmaceutical formulation was manufactured, bottled or packaged. 4.The pharmaceutical formulation of claim 1 comprising a coating.
 5. Thepharmaceutical formulation of claim 4, wherein the coating is a filmcoating.
 6. The pharmaceutical formulation of claim 4, wherein thecoating comprises the scent.
 7. The pharmaceutical formulation of claim1, wherein the scent is sequestered.
 8. The pharmaceutical formulationof claim 1, wherein the scent comprises a plurality of scents.
 9. Apharmaceutical formulation comprising an opioid and an imparted volatilescent, wherein the scent comprises less than 100 ppm of the dosage form,provides an olfactory effect which is physiologically unperceivable byhumans, is detectable by a non-human animal or an electronic olfactorymeasuring device, excludes perfluorocarbon tracers, and indicates whenand/or where the pharmaceutical formulation was manufactured, bottled orpackaged.
 10. The pharmaceutical formulation of claim 9, wherein theamount of the scent is detectable by the electronic olfactory measuringdevice.
 11. The pharmaceutical formulation of claim 9, wherein the scentindicates where the pharmaceutical formulation was manufactured, bottledor packaged.
 12. The pharmaceutical formulation of claim 9 comprising acoating.
 13. The pharmaceutical formulation of claim 12, wherein thecoating is a film coating.
 14. The pharmaceutical formulation of claim12, wherein the coating comprises the scent.
 15. The pharmaceuticalformulation of claim 9, wherein the scent is sequestered.
 16. Thepharmaceutical formulation of claim 9, wherein the scent comprises aplurality of scents.
 17. The pharmaceutical formulation of claim 9 whichis a tablet or a capsule.
 18. The pharmaceutical formulation of claim 1,wherein the scent is selected from the group consisting of volatileoils, synthetic flavor oils, flavoring aromatics, natural flavor oils,flavoring liquid oleoresins, flower extracts, fruit extracts, andcombinations thereof.
 19. The pharmaceutical formulation of claim 1,wherein the scent is selected from the group consisting of aldehydes,esters and mixtures thereof.
 20. The pharmaceutical formulation of claim1, wherein the scent is selected from the group consisting of anise,apple, arnica, balm mint, banana, basil, black pine, caraway, carnation,chamomile, cherry, Chinese cedar wood, chocolate, cinnamon, coconut,coffee, cypress, dill weed, eucalyptus, fir, fleurier, florogenia,forest ground, fresh baked bread, ginger bread, green apple, green bean,green spruce, hay flower, hazel, honey, hyacinth, incense, jacilia,jasmine, juniper, keymi, lavender, leather, lemon, lilac, lotus,mandarin, mango, maracuja, marjoram, May-flower, menthol, mixed alpineherbs, mugol, northern birch, ocean breeze, orange, orchid, ozone pine,peach, pear, petunias, pine, pinewood, pink pepper, pizza, plum, rose,raspberry, rosemary, sandalwood, sea breeze, Siberian spruce, spring,spruce pine, strawberry, thyme, tobacco, tomato, valerian, vanilla,violet, waffle, wild woodberry, musk, and mixtures thereof.
 21. Thepharmaceutical formulation of claim 1, wherein the scent is selectedfrom the group consisting of a fatty acid with short chains of two tosix carbon atoms, ketones, aldehydes, amines, o- and p-hydoxy benzoicacids and their esters, and combinations thereof.
 22. The pharmaceuticalformulation of claim 9, wherein the scent is selected from the groupconsisting of volatile oils, synthetic flavor oils, flavoring aromatics,natural flavor oils, flavoring liquid oleoresins, flower extracts, fruitextracts, and combinations thereof.
 23. The pharmaceutical formulationof claim 9, wherein the scent is selected from the group consisting ofaldehydes, esters and mixtures thereof.
 24. The pharmaceuticalformulation of claim 9, wherein the scent is selected from the groupconsisting of anise, apple, arnica, balm mint, banana, basil, blackpine, caraway, carnation, chamomile, cherry, Chinese cedar wood,chocolate, cinnamon, coconut, coffee, cypress, dill weed, eucalyptus,fir, fleurier, florogenia, forest ground, fresh baked bread, gingerbread, green apple, green bean, green spruce, hay flower, hazel, honey,hyacinth, incense, jacilia, jasmine, juniper, keymi, lavender, leather,lemon, lilac, lotus, mandarin, mango, maracuja, marjoram, May-flower,menthol, mixed alpine herbs, mugol, northern birch, ocean breeze,orange, orchid, ozone pine, peach, pear, petunias, pine, pinewood, pinkpepper, pizza, plum, rose, raspberry, rosemary, sandalwood, sea breeze,Siberian spruce, spring, spruce pine, strawberry, thyme, tobacco,tomato, valerian, vanilla, violet, waffle, wild woodberry, musk, andmixtures thereof.
 25. The pharmaceutical formulation of claim 9, whereinthe scent is selected from the group consisting of a fatty acid withshort chains of two to six carbon atoms, ketones, aldehydes, amines, o-and p-hydoxy benzoic acids and their esters, and combinations thereof.